B-cell-activating factor (BAFF) plays a role in mature B-cell generation and maintenance. Lipopolysaccharide (LPS) activates toll-like receptor 4 (TLR4)-dependent signal transduction and induces ROS production. Here, we investigated BAFF production regulated by reactive oxygen species (ROS). BAFF expression was augmented by LPS stimulation and by serum deprivation that induced ROS production. BAFF expression was inhibited by treatment with various antioxidants including N-acetyl-L-cysteine (NAC). We also investigated BAFF expression in vivo using peroxiredoxin II (PrxII)-deficient mouse spleen cells. PrxII is a member of the antioxidant enzyme family that protects cells from oxidative damage. Constitutive production of endogenous ROS was detected in spleen cells lacking PrxII. Serum BAFF protein level and BAFF transcript expression in splenocytes were significantly higher in PrxII(-/-) mice than wildtype mice. A higher BAFF level is consistent with the higher total number of splenocytes and B220(+)cells. Results were supported by NF-kappaB activation as judged by reduced IkappaBalpha degradation and increased nuclear translocation of p65/RelA with LPS stimulation, serum deprivation, and PrxII deletion. Data suggest that TLR4-mediated BAFF expression was increased by ROS and it was inhibited by PrxII controlling ROS production.